Christopher L. Amling

DEFINING PROSTATE SPECIFIC ANTIGEN PROGRESSION AFTER RADICAL PROSTATECTOMY: WHAT IS THE MOST APPROPRIATE CUT POINT?

PURPOSE The most appropriate definition of biochemical progression after radical prostatectomy and radiation therapy is uncertain. We analyzed the effect of using various prostate specific antigen (PSA) end point definitions for defining biochemical progression after radical prostatectomy and attempted to determine the best PSA cut point to use. Aspects of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure after radiation therapy are also analyzed in our radical prostatectomy cases. MATERIALS AND METHODS A total of 2,782 men with clinically localized prostate cancer (cT1-T2) who had undergone radical prostatectomy between 1987 and 1993 were reviewed. All patients had regular PSA determinations from surgery through followup. Analysis was limited to patients who did not receive adjuvant treatment within 90 days of radical prostatectomy. Biochemical, PSA progression-free percent after radical prostatectomy was determined by the Kaplan-Meier method using several PSA cut points, including 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater, as well as 0.4 ng./ml. or greater and increasing. Progression-free percent was also assessed using the ASTRO definition, which is 3 increases in PSA. To determine which PSA level was most appropriate to define progression after radical prostatectomy, the percentage of patients with a continued PSA increase after reaching each cut point was determined. The relationship between the maximum PSA within 3 years of surgery and subsequent development of clinical disease was also assessed. RESULTS Progression-free percent was dependent on the PSA cut point used. Biochemical progression-free percentages for cut points 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater were 62%, 72%, 76% and 78% at 5 years, and 43%, 54%, 59% and 61% at 10 years, respectively. A subsequent increase in PSA was noted in 49%, 62% and 72% of patients who had PSA 0.2, 0.3 and 0.4 ng./ml., respectively. Subsequent clinical progression (local or systemic) was directly related to the maximum PSA attained within 3 years of radical prostatectomy (p=0.0001). Progression-free percent for definitions requiring multiple increases in PSA were dependent on when the event was said to occur. Backdating of events at or before the first PSA (ASTRO definition) resulted in poorer, short-term progression-free percent (78% at 5 years), with little apparent likelihood of long-term failure (78% at 10 years). Coding the event at the last PSA increase when all event criteria had been met resulted in more realistic progression-free percent estimates (85% at 5 and 59% at 10 years). CONCLUSIONS Biochemical, PSA progression rates vary markedly depending on the method used to define PSA failure. Methods that require multiple increasing PSA values, for example the ASTRO definition, give misleading results, especially if the event time is backdated. Standards for defining PSA progression would allow more consistent and comparable progression estimates after radical prostatectomy. PSA 0.4 ng./ml. or greater may be the most appropriate cut point to use since a significant number of patients with lower PSA do not have a continued increase in it.

Pathologic Variables and Recurrence Rates As Related to Obesity and Race in Men With Prostate Cancer Undergoing Radical Prostatectomy

PURPOSE To determine if obesity is associated with higher prostate specific antigen recurrence rates after radical prostatectomy (RP), and to explore racial differences in body mass index (BMI) as a potential explanation for the disparity in outcome between black and white men. PATIENTS AND METHODS A retrospective, multi-institutional pooled analysis of 3,162 men undergoing RP was conducted at nine US military medical centers between 1987 and 2002. Patients were initially categorized as obese (BMI > or = 30 kg/m(2)), overweight (BMI 25 to 30 kg/m(2)), or normal (BMI < or = 25 kg/m(2)). For analysis, normal and overweight groups were combined (BMI < 30 kg/m(2)) and compared with the obese group (BMI > or = 30 kg/m(2)) with regard to biochemical recurrence (prostate-specific antigen > or = 0.2 ng/mL) after RP. RESULTS Of 3,162 patients, 600 (19.0%) were obese and 2,562 (81%) were not obese. BMI was an independent predictor of higher Gleason grade cancer (P <.001) and was associated with a higher risk of biochemical recurrence (P =.027). Blacks had higher BMI (P <.001) and higher recurrence rates (P =.003) than whites. Both BMI (P =.028) and black race (P =.002) predicted higher prostate specific antigen recurrence rates. In multivariate analysis of race, BMI, and pathologic factors, black race (P =.021) remained a significant independent predictor of recurrence. CONCLUSION Obesity is associated with higher grade cancer and higher recurrence rates after RP. Black men have higher recurrence rates and greater BMI than white men. These findings support the hypothesis that obesity is associated with progression of latent to clinically significant prostate cancer (PC) and suggest that BMI may account, in part, for the racial variability in PC risk.

EXTENSIVE REPEAT TRANSRECTAL ULTRASOUND GUIDED PROSTATE BIOPSY IN PATIENTS WITH PREVIOUS BENIGN SEXTANT BIOPSIES

PURPOSE Standard sextant prostate biopsy may underestimate cancer in men in whom clinical findings are suspicious for localized prostate cancer. We describe our experience with extensive transrectal ultrasound guided prostate biopsy in men in whom previous sextant biopsy was negative. MATERIALS AND METHODS Between November 1997 and March 1999, 57 men 47 to 72 years old (mean age 61.4) underwent extensive transrectal ultrasound guided biopsy of the prostate using intravenous sedation at our institution. An average of 22.5 cores (range 15 to 31) were obtained depending on prostate size. Biopsies were obtained from each of 6 sagittal regions, including samples from the far lateral and mid transitional zones. Each patient had undergone at least 1 previous benign transrectal ultrasound guided sextant biopsy (mean 2.1, range 1 to 4). Indications for repeat biopsy were persistently elevated prostate specific antigen (PSA) in 89% of the cases, increased PSA velocity in 63%, suspicious free-to-total PSA in 39% and a previous suspicious biopsy finding in 32%. Clinical factors (PSA, PSA velocity, free-to-total PSA and previous suspicious biopsy) were analyzed for the ability to predict positive biopsy, and tumor parameters were assessed pathologically in patients undergoing radical prostatectomy. RESULTS Adenocarcinoma was identified in 17 of the 57 men (30%). Biopsy revealed a Gleason score of 6 to 8 (mean 6.4). In 7 of the 17 patients (41%) in whom cancer was identified only 1 biopsy core was positive. Of the 15 patients in whom previous sextant biopsy had demonstrated high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation extensive biopsy revealed cancer in 7 (47%). Although serum PSA was higher and free-to-total PSA was lower in those with cancer, the only statistically significant predictor of positive biopsy was PSA velocity (p <0.001). Prostate cancer was noted in 64% of the men with PSA velocity 1 ng./ml. or greater. Of the 13 patients undergoing radical prostatectomy pathologically significant disease was identified in all but 1 (92%). Complications of extensive biopsy included urinary retention in 6 patients and limited rectal bleeding in 1. CONCLUSIONS Extensive prostate biopsy identifies significant prostate cancer in many men in whom previous sextant biopsy was benign. This procedure should be considered when findings are suspicious for adenocarcinoma despite previously negative sextant biopsy.

Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years.

PURPOSE Cure from malignancy is commonly defined as a disease-free state lasting 5 years after treatment. We analyzed clinical and biochemical progression rates after radical prostatectomy for men with clinically localized prostate cancer with particular attention to recurrence beyond 5 years. Annual hazard rates of progression were calculated to determine the probability of recurrence at specific intervals following surgery. MATERIALS AND METHODS The records of 2,782 men with clinically localized prostate cancer (cT1-T2) undergoing radical prostatectomy between 1987 and 1993 were reviewed. All patients were treated in the prostate specific antigen (PSA) era so that serial followup PSA values were available from the time of surgery. Analysis was limited to patients who did not receive adjuvant treatment within 90 days of radical prostatectomy. Disease progression was defined as documented local recurrence, systemic progression and/or PSA 0.4 ng./ml. or greater. Lymph node positive cases were eliminated from analysis since almost all received adjuvant hormonal therapy. Annual hazard rates for progression were calculated using the formula: [No. events / No. patients at risk] x 100. Progression-free survival probabilities were determined using the Kaplan-Meier method. RESULTS Pathological stage was pT2a-b, N0 (68%), pT3a, N0 (21%) and pT3b, N0 (11%). Biochemical progression-free survival at 5 and 10 years was 76% and 59%, respectively, for the entire study population while those with pathologically organ confined (pT2, N0) cancers had progression-free survival rates of 82% and 68% at 5 and 10 years, respectively. A total of 819 patients (29%) eventually had disease progression, including 160 (6%) with progression after 5 years. Annual hazard rates were highest during the first 2 years after radical prostatectomy for the entire population. Patients with adverse prognostic features (pT3b, PSA 10 ng./ml. or greater, Gleason score 8-10 and nondiploid cancers) had high initial hazard rates that decreased with time to lower levels. Those with pathologically organ confined cancer had low but constant hazard rates throughout followup. CONCLUSIONS Although progression after radical prostatectomy usually occurs early, reflecting the impact of clinical under staging, a significant number of men, including those with organ confined cancers, will continue to have disease progression after 5 years. Patients undergoing radical prostatectomy should be subjected to long-term followup to allow the option of early intervention should progression occur.

Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on outcome after radical prostatectomy

OBJECTIVES The impact of a positive surgical margin in otherwise confined prostate cancer after radical prostatectomy remains unclear. We analyzed the outcome of a large number of patients with organ-confined prostate cancer according to the presence and anatomic site of margin positivity. METHODS We evaluated 2712 prostatectomy patients with Stage pT2N0 cancer (ie, no evidence of extra-prostatic disease, seminal vesicle or regional node involvement) and no prior therapy who were treated by radical prostatectomy between 1987 and 1995 at Mayo Clinic. A total of 697 patients (26%) had positive margins. To assess the effect of margin status in the absence of treatment, 378 patients with postoperative adjuvant therapy were not considered for the study group: the final group consisted of 2334 patients. RESULTS Overall, 253 (58%) tumors were positive at the apex and/or urethra, 85 (19%) at the prostate base, 11 (2.5%) at the anterior prostate, and 174 (40%) at the posterior prostate; 89 (20%) had at least two margins involved and 21 (8.3%) had more than two involved. The apex/urethra was the only positive anatomic site in 183 (42%). Five-year survival free of clinical recurrence or prostate-specific antigen (PSA) biochemical failure (postoperative serum PSA of 0.2 ng/mL or more) for patients with a single positive margin was 79% for apex or urethra, 78% for anterior/posterior, and 56% for prostate base. Five-year survival free of clinical recurrence or PSA (biochemical) failure was slightly higher for those with one versus two margin-positive regions (77% versus 68%, respectively). Multivariate analysis revealed that positive surgical margins were a significant predictor of clinical recurrence and PSA (biochemical) failure (relative risk [95% confidence interval]: 1.65 [1.24, 2.18]) after controlling for Gleason grade, preoperative PSA, and deoxyribonucleic acid (DNA) ploidy. The effect of margin positivity on recurrence at a specific anatomic site (versus negative margins or positive at a different anatomic site) revealed the prostate base to be the only significant anatomic site when adjusted for grade, PSA, and ploidy. Five-year survival free of the combined clinical or PSA failure end point for those with versus those without positive margins at the prostate base was 56% versus 85%, respectively (P < 0.0001). CONCLUSIONS Positive surgical margins are a significant predictor of recurrence in Stage pT2N0 cancer, which is independent of grade, PSA, and DNA ploidy. The impact of positive margin status on recurrence-free survival appears to be anatomic and site-specific, with prostate base positivity significantly associated with poor outcome. The benefit of adjuvant therapy based on anatomic site-specific margin positivity remains to be tested in order to optimize recurrence-free survival.

Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy

PURPOSE Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach. MATERIALS AND METHODS Of 5,382 men in the database who underwent primary radical prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1,352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome. RESULTS Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05). CONCLUSIONS The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue.

Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy.

OBJECTIVES To define the utility of bone scan and computed tomography (CT) in the evaluation of patients with biochemical recurrence after radical prostatectomy. METHODS A retrospective analysis of the Center for Prostate Disease Research database was undertaken to identify patients who underwent radical prostatectomy between 1989 and 1998. Patients who developed biochemical recurrence (two prostate-specific antigen [PSA] levels greater than 0.2 ng/mL) and underwent either bone scan or CT within 3 years of this recurrence were selected for analysis. The preoperative clinical parameters, pathologic findings, serum PSA levels, follow-up data, and radiographic results were reviewed. RESULTS One hundred thirty-two patients with biochemical recurrence and a bone scan or CT scan were identified. Of the 127 bone scans, 12 (9.4%) were positive. The patients with true-positive bone scans had an average PSA at the time of the bone scan of 61.3 +/- 71.2 ng/mL (range 1.3 to 123). Their PSA velocities, calculated from the PSA levels determined immediately before the radiographic studies, averaged 22.1 +/- 24.7 ng/mL/mo (range 0.14 to 60.0). Only 2 patients with a positive bone scan had a PSA velocity of less than 0.5 ng/mL/mo. Of the 86 CT scans, 12 (14.0%) were positive. On logistic regression analysis, PSA and PSA velocity predicted the bone scan result (P <0.001 each) and PSA velocity predicted the CT scan result (P = 0.047). CONCLUSIONS Patients with biochemical recurrence after radical prostatectomy have a low probability of a positive bone scan (9.4%) or a positive CT scan (14.0%) within 3 years of biochemical recurrence. Most patients with a positive bone scan have a high PSA level and a high PSA velocity (greater than 0.5 ng/mL/mo).

Risk factors for vesicourethral anastomotic stricture after radical prostatectomy.

OBJECTIVES Preoperative comorbidities associated with microvascular disease may contribute to the development of bladder neck contracture (BNC) by alteration of anastomotic healing. We investigated potential risk factors for development of BNC after radical prostatectomy (RP) and reviewed management of this complication. METHODS A retrospective review of 467 consecutive patients (mean age 63.2 years) undergoing RP between 1991 and 1999 was performed. In all cases, the bladder neck was tailored to 20 to 22F in a racket handle fashion. After mucosal eversion of the reconstructed bladder neck, a mucosa-to-mucosa vesicourethral anastomosis was created over an 18 to 22F catheter using 4 to 6 anastomotic sutures. The relationship between comorbidities identified preoperatively by patient interview and medical record review (coronary artery disease [CAD], diabetes mellitus [DM], hypertension [HTN], cerebral vascular accident, chronic obstructive pulmonary disease, and smoking history) and the incidence of BNC was determined. Risk factors including prior transurethral prostatectomy (TURP), estimated blood loss (EBL), and operative time (OR time) were also evaluated. Factors were evaluated for their ability to predict BNC using both univariate and multivariate analysis. Treatment results for BNC were also assessed. RESULTS A total of 52 (11.1%) patients developed BNC. Current cigarette smoking resulted in a significantly higher (26%) rate of BNC (P <0.001). The BNC rate was also increased in patients with CAD (26%, P <0.001), HTN (19%, P = 0.015), and DM (21%, P = 0.030). Average OR time was longer (271 versus 249 minutes, P = 0.025) and EBL was greater (1639 versus 1092 mL, P <0.001) in patients developing a BNC. In multivariate analysis, current cigarette smoking was the strongest predictor of BNC and independent of other factors (P <0.001). BNC was not related to prior TURP, type of anastomotic suture used, size of catheter, or duration of catheterization. Patients were treated with transurethral dilation (73%) or transurethral incision (27%) and 58% responded to the initial treatment. No patient became incontinent as a result of the treatment for BNC.Conclusions. Several comorbidities associated with microvascular disease are significant risk factors for development of BNC after RP. Current cigarette smoking in particular is a strong predictor. Transurethral dilation and transurethral incision are equally effective as initial treatment of BNC.

Obesity, Serum Prostate Specific Antigen and Prostate Size: Implications for Prostate Cancer Detection

PURPOSE Obesity has been associated with lower serum testosterone, theoretically resulting in decreased PSA production. Obesity has also been associated with prostatic enlargement, making the detection of existent cancer more difficult. Together these findings would result in an apparent protective effect of obesity on prostate cancer risk due to technical detection issues unrelated to cancer biology. We examined the association between BMI, and PSA and prostate weight in a cohort of men undergoing RP. MATERIALS AND METHODS We evaluated the association of BMI with prostate weight and PSA using linear regression, adjusting for patient age at RP, year of RP, race, and pathological stage and grade in 1,414 men treated with RP between 1988 and 2004 at the 5 equal access medical centers that comprise the Shared Equal Access Regional Cancer Hospital Database. RESULTS On multivariate analysis increasing BMI was associated with increasing prostate weight but only in men younger than 63 years and not in men 63 years or older (p-trend <0.001 and 0.44, respectively). In men younger than 63 years mean multivariate adjusted prostate weight +/- SE in those with a BMI of less than 25 vs 30 to 34.9 kg/m was 33.8 +/- 1.4 vs 41.4 +/- 1.6 gm. There was no significant association between BMI and preoperative PSA (p-trend = 0.70). CONCLUSIONS In a cohort of men undergoing RP obesity was associated with larger prostate size but only in younger men. There was no association between BMI and PSA. Assuming equal PSA, the degree of prostatic enlargement observed in younger obese men in this study would be expected to result in a modest decrease in the odds of detecting prostate cancer in a contemporary series of PSA screened men due to the decreased sensitivity of cancer detection related to larger prostate size. Obesity may appear protective for prostate cancer in younger men due to technical issues unrelated to cancer biology.

DEOXYRIBONUCLEIC ACID PLOIDY AND SERUM PROSTATE SPECIFIC ANTIGEN PREDICT OUTCOME FOLLOWING SALVAGE PROSTATECTOMY FOR RADIATION REFRACTORY PROSTATE CANCER

PURPOSE We assessed clinical and pathological variables for the ability to predict improved outcome following salvage prostatectomy for radiation refractory prostate cancer. We identify factors that might assist in selection of candidates for this procedure. MATERIALS AND METHODS Between 1966 and 1996, 108 patients (mean age 64.7 years) underwent salvage radical retropubic prostatectomy for radiation refractory prostate cancer. Preoperative serum prostate specific antigen (PSA), available in 70 patients treated since 1987, was less than 4 in 19, 4 to 10 in 31 and greater than 10 ng./ml. in 20. Serum PSA before radiotherapy was available in 37 patients. Serum PSA before radiotherapy and salvage surgery, tumor grade, deoxyribonucleic acid (DNA) ploidy and margin status were analyzed for the ability to predict cancer specific and progression-free survival (local, systemic and PSA 0.2 ng./ml. or greater). Complication rates were compared between early (before 1990) and late (1990 to 1996) salvage prostatectomy groups. RESULTS Overall cancer specific and progression-free survival at 10 years was 70 and 44%, respectively. The pathological stage was pT2N0 in 39%, pT3-4N0 in 42% and pTxN+ in 19% of cases. DNA ploidy was predominately nondiploid, that is diploid in 25%, tetraploid in 64% and aneuploid in 11% of tumors. Although preoperative serum PSA was not predictive of pathological stage, patients with preoperative PSA less than 10 ng./ml. had better progression-free survival than those with higher levels (p = 0.05). DNA ploidy was the strongest predictor of cancer specific (p = 0.002) and progression-free (p = 0.002) survival. Controlling for grade and PSA using the Cox proportional hazards model, DNA ploidy remained a significant predictor of prostate cancer death (p <0.001) and disease progression (p <0.001). Complication rates improved somewhat in more recently treated patients but incontinence and bladder neck contracture rates remained significant. CONCLUSIONS DNA ploidy and preoperative serum PSA appear to be the most important predictors of outcome following salvage prostatectomy for radiation refractory prostate cancer. Preoperative consideration of these factors may be helpful in selecting candidates for this procedure.